Potentiating microglial efferocytosis by MFG-E8 improves survival and neurological outcome after successful cardiopulmonary resuscitation in mice.

Abstract

Brain injury represents the leading cause of mortality and disability after cardiopulmonary resuscitation (CPR) from cardiac arrest (CA), in which the accumulation of dying cells aggravate tissue injury by releasing proinflammatory intracellular components. Microglia play an essential role in maintaining brain homeostasis via milk fat globule epidermal growth factor 8 (MFG-E8)-opsonized efferocytosis, the engulfment of dying cells and debris. This study investigates whether potentiating microglia efferocytosis by MFG-E8 provides neuroprotection after CA/CPR. After 8-minute asphyxial CA/CPR, male adult C57BL/6J mice were randomly assigned to receive recombinant mouse MFG-E8 (rmMFG-E8) or vehicle. We evaluated the survival and neurological deficits of mice, along with histological damages, phagocytosis index of dying cells, and microglia polarization. A transcriptome analysis was conducted to explore the downstream molecules modulated by MFG-E8. In mice resuscitated from CA, rmMFG-E8 administration significantly enhanced the efferocytosis of apoptotic cells by microglia, improved the survival and neurological function of mice, and attenuated neuropathological injuries. Additionally, rmMFG-E8 induced a prominent alteration in microglial gene expression and promoted a shift from a proinflammatory phenotype to an anti-inflammatory phenotype. Moreover, rmMFG-E8 treatment induced up-regulation of interferon regulatory factor 7 (IRF7), and IRF7 gene silencing largely reversed the neuroprotective effects of rmMFG-E8. This study demonstrates that rmMFG-E8 improves survival and neurological outcomes after CA/CPR by enhancing microglial efferocytosis and reshaping the inflammatory microenvironment in brain tissue. Potentiating MFG-E8 is a promising strategy to combat post-CA brain injury.